In the reaction between trans-diamminedichloroplatinum(II) and a single-stranded pyrimidinerich oligodeoxyribonucleotide (22-mer) containing the central sequence TGAGT, the 1,3-trans-{Pt(NH3)2[d(GAG)J} crosslink is formed. The 1,3-intrastrand cross-link is inert within the single-stranded oligonucleotide. In contrast, it rearranges to an interstrand cross-link when the platinated oligonucleotide is paired with its complementary deoxyribo-or ribonucleotide strand. The half-life of the 1,3-intrastrand cross-link, -6 h at 370C, is independent of the nature and concentration of the salt (NaCl or NaCI04). It is not dramatically affected when the intervening adenine residue between the chelated guanine residues is replaced by a cytosine or a thymine residue or when the TA base pair adjacent to the 5' or 3' side of the adduct is replaced by a C-G base pair. On the other hand, a mismatch on the 3' or 5' side of the adduct prevents the rearrangement. We propose that the linkage isomerization reaction results from a direct nucleophilic attack of the cytosine residue complementary to the platinated 5' guanine residue on the platinum residue. Among others, the potential use of the DNA RNApromoted reaction is discussed in the context of the antisense strategy to irreversibly cross-link the antisense oligonucleotides to their targets. cis-Diamminedichloroplatinum(II) (cis-DDP) is a chemotherapeutic agent used largely in the clinical treatment of tumors. It is generally accepted that the cytotoxic action of cis-DDP is related to its ability to bind to cellular DNA and form covalent adducts. Although the major lesion is an intrastrand cross-link between two guanine (G) residues, it is not yet established that this lesion is responsible for the antitumor activity of cis-DDP (for general reviews, see refs. 1-4). Acquired resistance to cis-DDP may be associated with the increased gene-specific DNA repair efficiency of the interstrand adducts (5), a minor lesion in which the two G residues in the d(GC)-d(GC) site are cross-linked (6, 7).A question still under debate concerns trans-dichlorodiammineplatinum(II) (trans-DDP), the stereoisomer of cis-DDP. This compound is less mutagenic and less cytotoxic than cis-DDP and is ineffective as an antitumor drug (1)(2)(3)(4). In their reaction with DNA, the two isomers present similarities and differences (for general reviews, see refs. 8 and 9). The DNA modification by cis-or trans-DDP is controlled kinetically and the adducts are formed in two solvent-assisted reactions. The exchange of the chloro groups of both isomers is rate-limiting in both the initial attack of DNA and the closure of monofunctional adducts to bifunctional crosslinks. The preferred site of initial binding of the isomers is the N7 atom of G residues. Subsequently, the monofunctional adducts react with the neighboring bases to form intrastrand and interstrand cross-links. Among the differences between the two isomers, one is that stereochemical limitations preclude trans-DDP from forming intrastrand cross-links b...